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Wavelet based analysis for mass spectrometry (MS) profiles of three groups of patients are analyzed for the purpose of developing a classification model. The first step in our model uses a DWT for feature extraction, using a linear combination of Symlets, Daubechies and Coiflets wavelet bases – collectively known as a super wavelet. Random Forests and Treeboost are then used to analyze the super wavelet coefficients to form the classification model. The method is illustrated using the publicly available prostate SELDI-TOF MS data from the American National Cancer Institute (NCI). The NCI data consists of 322 MS profiles with 15154 M / Z ratios, comprising of 69 malignant, 190 benign and 63 control patients, which we randomly divided into 70% training and 30% testing. From the Random Forest models, the super wavelet performed 2.7% to 5.7% better than other single wavelet types to give a 100% test set prediction rate for cancerous patients.

A novel series of potent blockers of the monocarboxylate transporter, MCT1, is disclosed. From very potent but lipophilic lead compounds, systematic changes to all parts of the molecule, targeting reduction in log D, afforded compounds with significantly improved overall properties. These compounds show potent immunomodulatory activity.

Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.

We introduce a new method of unsupervised cluster exploration and visualization for spectral datasets by integrating the wavelet transform, principal components and Gaussian mixture models. The Bayesian Information Criterion (BIC) and classification uncertainty performance criteria are used to guide an automated search of commonly available wavelets and adaptive wavelets. We demonstrate the effectiveness of the proposed method in elucidating and visualizing unsupervised clusters from near infrared (NIR) spectral datasets. The results show that informative feature extraction can be achieved through both commonly available wavelet bases and adaptive wavelets. However, the features from the adaptive wavelets are more favorable in conjunction with unsupervised Gaussian mixture models through a user specified internal linkage function.

The rearing and maintenance of wildvicunas in semi-captivity for economicutilization is practiced mainly in Peru, butArgentina, Bolivia, and Chile are quicklydeveloping their own programs of economic use. Large scale rearing practices will likelyisolate populations and may foster selectivebreeding. In addition to these concerns, thereare also uncertainties about the distributionand validity of the currently recognizedsubspecies. To better understand the potentialimpact that economic utilization will have onthe vicuna, we describe the moleculargenetic variation among four populations andboth described subspecies. An analysis of 794~bp of mitochondrial DNA sequences (16s,cytochrome b genes, and mtDNA control region)revealed appreciable genetic diversity, low tomoderate levels of genetic differentiation, andrestricted gene flow with isolation by distanceamong populations. Analysis of microsatellitedata also indicated genetic differentiationamong populations. Past climatic and geologicevents, coupled with human history, have likelysubjected the vicuna to various episodes ofpopulation isolation and admixture. Therefore,we suggest that managers aim to ensure geneflow among adjoining populations, as observedat mtDNA and microsatellite loci, as well asmaintaining apparent restricted gene flow withisolation by distance among populationsseparated by great distances. Intensiverearing procedures like those being practicedin Peru will ultimately disrupt movements andmigration among wild populations. Furthermore,animals that are not exposed to predation byremaining inside fences, may overtime, loseportions of their behavioral repertoire thatenable them to recognize potentially dangeroussounds associated with the presence ofpredators. Therefore, we do not recommend thatanimals be placed behind fences as this couldlead to a loss of genetic and behavioraldiversity as well as halting natural ecologicalprocesses. If, however, vicunas are placedbehind fences for commercial purposes (withlittle or no regard for the retention ofgenetic, and/or behavioral diversity as well asnatural population processes) then we suggestclose genetic monitoring of animals that are(will be) maintained in captivity.

General methods are descibed for the synthesis of mesoionic derivatives of [1,2,3]triazolo[1,5-a]quinoline, [1,2,3]triazolo[1,5-a]quinazoline, [1,2,3]triazolo[1,5-a]quinoxaline and [1,2,3]triazolo[5,1-c]benzotriazine.

In this article, Kimberley Porteus and colleagues analyse the factors underlying school non-attendance in three poor, marginalised communities in South Africa. The findings reveal that ‘poverty’, including the interaction between physical, social and psychological factors, has by far the greatest influence on children's being out of school. The study concludes that poverty needs to be addressed as a priority if the very notion of ‘inclusion’ is to have meaning in South African society.

Background. The study was conducted in an educationally disadvantaged South African community where the effectiveness of a paired reading parent involvement programme, which stressed interaction around reading as a means of mediating meaning, was evaluated. Aims. The research aimed to evaluate whether reading accuracy, comprehension and attitude were promoted through involving parents and other family members as mediators in a process of paired reading. Further, it aimed to elucidate interactive ecosystemic effects across family, school and community levels. Samples. Two complete grade four classes (29 and 32 children respectively) served as comparison groups (average age: 9 years 7 months). Methods. To test the significance of the improvement in reading accuracy and comprehension (Neale Analysis of Reading Ability: Neale, 1966) and attitude (Elementary Reading Attitude Survey: McKenna & Kear, 1990) for the experimental group relative to the control, one-tailed t-tests for independent samples on the respective pre-test/post-test difference scores were applied. Results. Statistically significant improvements in reading accuracy and comprehension, as well as reading attitude and involvement, were demonstrated. A broad ecosystemic analysis suggested that positive relationships between children and significant others in the family were nurtured and other children in the family were benefiting. Interactions between family and school, and school and the local community library, were also enhanced. Conclusions. The study emphasises the importance of developing mediation insights and skills in parent involvement programmes, and the place of ecosystemic analysis in understanding the social dynamics involved in such programmes.

The business firm carries the burden of delivering many aspects of "the satisfactory life" in the developed world of the late twentieth century. It is a fundamental unit of social organization. Analogous in many ways to the family, it takes many forms, can be defined in several different ways, and performs a multiplicity of direct and indirect functions. While most evidently economic in character, firm interactions with, and impact on, social life are considerable and are an important feature of the politics of capitalist societies. In its modern forms, the firm created by political actions in the past century and a half (in Britain and especially by the Joint Stock Companies Act of 1856) is enshrined in a complex set of laws and practices. 1 In the wake of the "great capitalist restoration," it is interesting to consider the politics of the capitalist firm in the political economy of late twentieth century Britain.

Research on South African street children has pointed to an apparent paradox in terms of vulnerability and resilience, requiring a closer examination of how street children make meaning of their lives as well as the contexts in which these meanings are constructed. This study makes use of a variety of data, including drawings, stories and spontaneous drama to access commonly manifested themes and patterns of interaction among a small group of ex-street children attending a voluntary, non-formal learning centre in Cape Town. Over four months of participant observation, consistent themes and patterns of interaction were identified and interpreted in terms of shortterm adaptation and/or longer-term protection or risk within the overall context. The most consistent tendencies towards resilience involved themes of autonomy and the power to control events, both closely related to themes and patterns of peer group solidarity. Within the context, tendencies towards risk were closely integrated with the above. Combined with a general suspicion and wariness of adults, the drive for autonomy, in particular, was in conflict with signs of underlying insecurity and tended to undermine the development of relationships with potentially caring adults.

The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.

Given the nature and the extent of the problem, the psychological and developmental implications of the street child phenomenon in South Africa needs to be more closely examined. Current research on street children presents us with a paradox — with evidence of developmental risk and vulnerability on the one hand and of resourcefulness, adaptability and coping on the other. This paradoxical evidence is reviewed from the perspective of physical, emotional, social and cognitive/educational development. Implications for intervention are explored. In particular, the issue of what defines developmental vulnerability or resilience in more specific terms is identified as a research necessity if more focused intervention priorities are to be determined.

A number of FKBP12 ligands were designed and synthesised and their affinity for FKBP12 assessed. In these ligands the pyranose ring of FK506 was replaced by other more synthetically accessible groups. The preparation of suitable intermediates for the synthesis of “dual domain” inhibitors (compounds 6a–c, 15 and 22) is also described.

A number of dual domain, macrocyclic FKBP12 ligands were synthesised in which the FK506 effector domain was fused to simplified FKBP12 bindings domains. The resulting macrocyclic compounds possessed moderate binding affinities for FKBP12 but showed no activity in an assay for FKBP12 dependent calcineurin inhibition.

The affinity of a non macrocyclic analogue of FK506 for the immunophilin FKBP12 was determined The affinity of this analogue/FKBP12 complex for calcineurin was studied.

Beckmann rearrangement of FK506 E-oxime gave amide 2 and the fragmentation product 4 . Compound 4 was also prepared by total synthesis.

General methods are descibed for the synthesis of mesoionic derivatives of [1,2,3]triazolo[1,5-a]quinoline, [1,2,3]triazolo[1,5-a]quinazoline, [1,2,3]triazolo[1,5-a]quinoxaline and [1,2,3]triazolo[5,1-c]benzotriazine.

Signals are all around us! Electromagnetic broadcasts permeating the air, stock market ticker-tape on the floor, Voyager space probe emissions streaming into the universe, and electrical pulses through human nerves – all are different types of signals. Signals are broadly defined as a sequence of measurements that can either be continuous or discrete. Often, sequences are captured at varying intervals in time, frequency, wave numbers, or distance. (While introducing ideas about wavelets and how they can be applied in chemical settings, for simplicity and generality let us consider a signal to be a function of time.) A signal of particular interest is the absorption or reflection of electromagnetic radiation measured in intervals of wavelength, as this signal is characteristic of the chemical and physical composition of the substance being measured. Another property of signals is if two or more signals overlap, then the resulting overlap is also a signal. This signal addition is usually an undesirable property as it is usually impossible to measure the individual signals independently of each other. A classic example is when a sample contains two molecules having similar absorbance signals – absorption signals with overlapping wavelength regions. When the absorption signal of the sample is measured, a combination of the two absorption signals is recorded simultaneously. The addition of signals poses a problem when information regarding only one of the two molecules is sought. Sequential measurement and signal addition are essential principles for the analysis of signals. First, the sequential principle gives a signal a quintessential ‘shape’ and, second, signal addition distorts a sought-after signal/shape by the presence of other signals. Ideally, any method for the analysis of signals should aim at extracting the components of a signal such as expressing the signal as a series of shapes. Wavelet analysis incorporates the principles of both signal addition and sequential shape representation, making wavelets a suitable method for signal analysis. Wavelet analysis represents signals by a series of orthogonal basis functions. In Fourier analysis, the basis function is the sinusoidal function, whereas in wavelet analysis, the basis function is largely undefined with the exception that the basis function is localized and orthogonal onto itself upon translation or dilation. This flexibility of wavelet basis functions enables a wide range of signal shapes to be investigated within the context of signal addition. There exist a large suite of functions that fit the wavelet description such as the derivatives of the Gaussian, and because of the popularity of wavelets in the 1990s and 2000s, there exist a large variety of standard wavelet basis to choose from. Some of these basis functions have been given names such as Daubechies wavelets, Coiflets, the Haar wavelet, and the Mexican wavelet. The choice of the wavelet basis is an important issue because the basis function is typically meant to mimic localized information embedded in the signal. The chemometricians can investigate the performance of some of the ‘famous’ wavelet basis functions, or they can design their own wavelet basis functions. The latter allows wavelet basis functions to be designed to suit both the data set and subsequent analysis method. The objective of this chapter is to demonstrate how wavelet basis functions can be computed for a range of multivariate statistical tasks such as unsupervised mapping (Section 3.23.3.1), discriminant analysis (Section 3.23.3.2), regression analysis (Section 3.23.3.3), and multivariate analysis of variance (MANOVA) (Section 3.23.3.4). Following a description of the wavelet theory in Section 3.23.2, the extension to adaptive wavelets is described in Section 3.23.2.7. Section 3.23.3 surveys the statistical methods that utilize the adaptive wavelet coefficients, and Section 3.23.4 puts all the above to practice by providing worked examples of the adaptive wavelet feature transformation procedure using near-infrared (NIR) spectra.

Three C-10 N-Acyl derivatives of FK-506 have been prepared. The reduced receptor binding of these analogues is not consistent with a direct overlap of FK-506 and a peptide substrate.

Given the predominance of needs within the non-privileged sector of South African society, two major issues face those who train in the field of educational psychology: the issue of how to train in sufficient numbers and the issue of the content and process of training where relevance and effectiveness are in question. With 77% of the school-going population having only one educational psychologist available for every 30 000 pupils, the needs cannot be met only through the current highly specialized and protracted training. The concept of a dual model of training with mental health workers also being trained to meet cross-disciplinary, basic level needs is developed. In conjunction with this, process and content shifts in training at both levels are suggested in order to meet three major areas of need: special education and the needs of those with developmental and educational disabilities; underachievement in black education; and problems resulting from the breakdown of families and effective parenting.

A copper-catalysed migratory insertion reaction was used to construct the tri-substituted alkene of the C16-C23 segment 4 of the potent immunosuppressant FK-506 (Tsukubaenolide) (1).

Novel small molecular weight compounds that act by inhibiting the monocarboxylate transporter (MCT1) receptor have been found to cause profound inhibition of T-cell responses to alloantigen in vitro. Here, we have investigated the ability of one compound in this series, AR-C117977, a potent MCT1 inhibitor, to prevent the acute and chronic rejection of vascularized and nonvascularized allografts in the mouse. Treatment with AR-C117977 or cyclosporin A (CsA) administered at a dose of 30 mg/kg subcutaneously for 15 days to adult CBA. Ca (H2(k)) mice, commencing either 3 days or 1 day before transplantation, was found to prolong the survival of an allogeneic (C57BL/10 H2(b); NZW H2(z); or BALB/c H2(d)) heart, aorta, or skin allograft significantly compared with treatment with vehicle alone (median survival time [MST] AR-C117977 treated 15; 19 and 18 days [skin] and 73; 66 and 67 days ([heart] vs. vehicle treated 8, 8 and 9 days [skin] and 9, 8, 10 days [heart] for B10, NZW and BALB grafts, respectively). AR-C117977 also inhibited the development of transplant arteriosclerosis in aortic allografts partially, but was unable to inhibit alloantibody production after transplantation. The specific MCT1 inhibitor AR-C117977 has potent immunosuppressive properties in vivo effectively preventing acute but not chronic allograft rejection in the mouse.

A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.

The reaction between N-hydroxyphthalimide and optically pure epichlorohydrin followed by addition of methanol represents a straightforward procedure for the synthesis of isoxazolidin-4-ols in high enantiomeric purity. Under the same conditions, the reaction of glycidyl arenesulfonates can lead to different products depending on the nature of the sulfonate. This property allowed the synthesis of both enantiomers of 4-methylisoxazolidin-4-ol from the same chiral epoxide starting material.

The synthesis and pharmacological evaluation of a new series of potent P2X 7 receptor antagonists is disclosed. The compounds inhibit BzATP-mediated pore formation in THP-1 cells. The distribution of the P2X 7 receptor in inflammatory cells, most notably the macrophage, mast cell and lymphocyte, suggests that P2X 7 antagonists have a significant role to play in the treatment of inflammatory disease.